Experimental drug shown to block mutant protein causing blood disease

’Targeted’ drug might treat skeletal disorders and cancers

Scientists at Dana-Farber Cancer Institute and Brigham and Women’s Hospital have prolonged the lives of mice with a rare blood disorder by using an experimental drug that blocks signals promoting runaway growth of blood cells. The researchers also tested the drug, PKC412, in a patient with the hard-to-treat disease, called Myeloproliferative Disease (MPD), and saw her symptoms improve.

PKC412, like the spotlight drug Gleevec, is a highly specific “targeted” drug that disables a switch in cancer cells that has become jammed in the “on” position because of a genetic mutation. The glitch allows a continuous stream of signals to prod blood cells into an uncontrolled frenzy of division and growth. The overproduction of white blood cells in MPD damages organs and generally turns into an acute leukemia that can be fatal.

The report appears in this week’s Online Early Edition of the Proceedings of the National Academy of Sciences. Jing Chen, PhD, of Brigham and Women’s, and Daniel J. DeAngelo, MD, PhD, of Dana-Farber, are the paper’s co-first authors. D. Gary Gilliland, MD, PhD, a Howard Hughes Medical Institute investigator at Brigham and Women’s Hospital, and Richard M. Stone, MD, of Dana-Farber are the senior authors. Other authors are from Dana-Farber, Brigham and Women’s, Harvard Medical School, Emory University, and Novartis Pharma AG. “The study shows the potential utility of drugs that block mutant tyrosine kinases, and that these drugs are opening more doors to treating cancers,” explains Stone.

Tyrosine kinases are molecules that act as biological switches inside cells, regulating processes including cell division and growth. Abnormal kinases have been discovered to be major culprits in many forms of cancer. Because inhibitor drugs strike the abnormal kinases in cancer cells without harming normal tissue, they are associated with fewer side effects than standard cancer drugs.

In the study, mice with MPD that were treated with the oral compound PKC412 significantly outlived those given a placebo. When tested in a single patient, a 52-year-old woman with MPD, the drug reduced her dangerously high white blood cell count and shrank her enlarged spleen and lymph nodes. However, the disease wasn’t cured and she underwent a bone-marrow transplant to treat the acute leukemia caused by her MPD.

PKC412 acts similarly to the pioneering drug Gleevec, one of the first drugs to treat cancers by shutting down abnormal kinase signal switches. Gleevec blocks uncontrolled growth signals in Chronic Myelogenous Leukemia and Gastrointestinal Stromal Tumor.

The Dana-Farber scientists have been testing PKC412 in patients with Acute Myeloid Leukemia, some cases of which are caused by a mutant on-off switch called FLT3. The drug specifically blocks abnormal FLT3 kinases.

MPD is caused by a different mutated kinase, FGFR1, which is inhibited by PKC412. The mutation occurs when two broken pieces of the chromosome that carries the FGFR1 gene join together abnormally.

The findings suggest, the authors write, that PKC412 may be effective in treating MPD, as well as other diseases and cancers where mutant FGFR1 is the culprit. These include human skeletal disorders such as Pfeiffer syndrome, which causes misshapen skull, face, fingers and toes, breast and pancreatic cancers, and brain tumors.